The principal aim of this proposal is to deliver a sustained release, polymeric agent to prevent collagen accumulation in hypertensive blood vessels. The polymer, a backbone of alternating PEG2000 and lysine with the proline analogue cis-4-hydroxy-L-prol ine (cHyp) attached to the lysine group, has sustained, specific antifibrotic activity. It is proposed to redesign the polymer by using PEG1000 in place of PEG2000 to increase drug "loading" of the polymer. Because of the size of the p olymer (Mr=21,000d), liposomes are required for uptake by endothelial cells and a polysaccharide -coated liposome will be employed to enhance cell uptake. Retention of the polymer/liposome delivery system will be tested using an endothelial cell/smooth muscle cell (SMC) coculture system. Uptake of the delivery system by endothelial cells, stability of the polymer in cells and release of the active agent to SMCs to inhibit collagen synthesis will be studied. Another experiment will evaluate the effects of i.v. infused polymer in polysaccharide-coated liposomes on vascular collagen accumulation and pulmonary hypertension in rats exposed to hypoxia (10% O2). Results will be compared to treatment with nonbioactive trans-Hyp polymer. The strategy to locally deliver a sustained release collagen inhibitor may be applied to various fibrosing disorders.